The purpose of this grant is to allow the candidate to receive training in new research areas including medical and statistical genetics and behavioral animal modeling. Additional training in these areas will substantially add to the research capabilities of the applicant allowing her to successfully establish an independent research career. The candidate's training will take place under the joint supervision of Drs. T. Bird, R. Palmiter, and W. Raskind at the University of Washington. This interdisciplinary training is proposed in the context of a unique study which evaluates the genetic contributions of parkin and tau (MAPT) to neurofibrillary tangle (NFT) formation in Progressive Supranuclear Palsy (PSP) and to NFT formation in a novel animal model of neurodegenerative disease. PSP is a rare neurodegenerative disorder characterized by parkinsonism, postural instability, and supranuclear gaze palsy. PSP is generally a sporadic disorder; however, familial clustering has been reported, suggesting that heritable genetic components contribute to the onset or progression of disease. Association of the MAPT H1 haplotype with PSP, presents MAPT as a candidate gene for PSP; however, coding sequence MAPT mutations in PSP are rare. The candidate has identified a heterozygous P437L mutation inparkin in a PSP subject with a previously identified tau R5L mutation. Subsequent evaluation of a single nucleotide polymorphism (SNP) within intron 2 (12) of parkin in a panel of 179 PSP subjects revealed a genetic association with a specific genotype in the PSP population vs. controls (p=0.0028). Mutations or polymorphisms within parkin may contribute to the onset or progression of disease in PSP. Preliminary animal model data (MiPrtransgenic mice on a parkin null background) support this theory, where over-expression of human tau and loss of parkin results in the formation of insoluble tau. The objectives of this project are: 1) to identify potential interactions between parkin mutations/SNPs/haplotype blocks and known MAPT H1 haplotype data in PSP using linear regression analysis, 2) to identify and determine the significance of parkin gene mutations in PSP subjects, and 3) to characterize the roles of tau and parkin in the formation of insoluble tau and NFTs in a mouse model of PSP. Identification of parkin risk alleles that contribute to NFT formation may provide insights into a number of multi-factorial age-related neurodegenerative diseases.